Abstract
In this study, we investigated the antitumor effects of the tricyclic antidepressant 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine (imipramine) on glioma cells. We found that exposure of U-87MG cells to imipramine resulted in the inhibition of PI3K/Akt/mTOR signaling, reduction of clonogenicity, and induction of cell death. Imipramine stimulated the formation of acidic vesicular organelles, the conversion of LC3-I to LC3-II, and the redistribution of LC3 to autophagosomes, suggesting that it stimulates the progression of autophagy. It did not, however, induce apoptosis. We further showed that knockdown of Beclin-1 using siRNA abrogated imipramine-induced cell death. These results suggest that imipramine exerts antitumor effects on PTEN-null U-87MG human glioma cells by inhibiting PI3K/Akt/mTOR signaling and by inducing autophagic cell death.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antidepressive Agents, Tricyclic / pharmacology*
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Antineoplastic Agents / pharmacology*
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Apoptosis Regulatory Proteins / genetics
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Autophagy / drug effects*
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Autophagy / genetics
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Beclin-1
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Cell Line, Tumor
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Gene Knockdown Techniques
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Glioblastoma / enzymology*
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Humans
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Imipramine / pharmacology*
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Membrane Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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PTEN Phosphohydrolase / genetics
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Rats
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TOR Serine-Threonine Kinases / antagonists & inhibitors
Substances
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Antidepressive Agents, Tricyclic
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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MAP1LC3A protein, human
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Membrane Proteins
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Microtubule-Associated Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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PTEN Phosphohydrolase
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Imipramine